Enantiomerically pure substituted oxaaza compounds, salts of the same, and processes for the preparation of both

ABSTRACT

This invention provides a method for conveniently obtaining a compound of formula (Ia) which is a production intermediate of antimicrobial compounds, in which a salt of optically active acid of formula (IIIa) is obtained by allowing a compound of formula (I), a ketone compound and an optically active acid to react with one another, converted into its free form and then hydrolyzed.                    
     In the formula, R 1 : hydrogen atom or alkyl, aryl or aralkyl group; R 2 : hydrogen atom or alkyl, aryl, aralkyl, acyl, alkyloxycarbonyl, aralkyloxycarbonyl or substituted sulfonyl; these may further have substituents.)

TECHNICAL FIELD

This invention relates to a production intermediate of antimicrobialcompounds and a production method thereof.

BACKGROUND ART

3-Amino-4-fluoromethylpyrrolidinyl group is useful as substituent ofquinolone compounds. This substituent exists in four stereoisomer formsoriginated from the configuration of amino group and fluoromethyl groupon the pyrrolidine ring. That is, it exists in two isomers of cis andtrans forms, and each of them exists in stereoisomer forms havingenantiomorphic relationship, thus existing in four isomer forms. Mostuseful among these four isomers is(3S,4S)-3-amino-4-fluoromethylpyrrolidinyl group represented by thefollowing formula:

which has one of the enantiomorphic relationship of cis configurationand can provide a quinolone having excellent antimicrobial activity andsafety.

In order to introduce this (3S,4S)-3-amino-4-fluoromethylpyrrolidinylgroup into a quinolone compound,(3S,4S)-3-amino-4-fluoromethylpyrrolidine (formula (Va)):

or a derivative thereof is required. In order to obtain this(3S,4S)-3-amino-4-fluoromethylpyrrolidine or a derivative thereof, it isconvenient to obtain (3S,4S)-3-amino-4-hydroxymethylpyrrolidine (formula(IVa)):

or a derivative thereof and introduce fluorine atom into the compound.

However, though cis-3-amino-4-hydroxymethylpyrrolidine as its racemiccompound has been known, a method for the synthesis of(3S,4S)-3-amino-4-hydroxymethylpyrrolidine has not been known.Accordingly, the object of the invention of this application is toprovide an efficient method for the production of(3S,4S)-3-amino-4-hydroxymethylpyrrolidine or a derivative thereof whichis an excellent substituent supply source for efficiently obtainingexcellent quinolone compounds.

DISCLOSURE OF THE INVENTION

As a result of extensive investigation, the present inventors have foundthat, when a racemic cis-3-amino-4-hydroxymethylpyrrolidine derivativerepresented by formula (I) is treated with mandelic acid as an opticallyactive compound in acetone (or in the presence of an appropriate ketonecompound), a condensed 1,3-oxazine derivative (III) is formed throughthe progress in an acetone- (or an appropriate ketone compound)-relatedring closure reaction between the amino group and hydroxymethyl group,and one of the isomers of this compound forms a salt with the opticallyactive mandelic acid and precipitates as crystals.

That is, it was revealed that separation of enantiomers of the compoundof formula (I) is achieved by the precipitation of a salt of the oxazinecompound represented by formula (III) with the optically active mandelicacid as crystals. In addition, it was revealed also that, when this saltis converted into its free form by removing mandelic acid and thenhydrolyzed, a 3-amino-4-hydroxymethylpyrrolidine derivative comprised ofone of the enantiomers is easily regenerated through ring opening of theoxazine ring.

Namely, the present invention was accomplished by finding that one ofthe enantiomers of the 3-amino-4-hydroxymethylpyrrolidine derivative canbe obtained easily in this manner.

Accordingly, the present invention relates to a compound represented bythe following formula (IIIa):

or formula (IIIb):

[in the above formulae,

R¹ represents

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),

an acyl group (which may be either aliphatic or aromatic; in the case ofan aliphatic group, it has from 1 to 7 carbon atoms and may have one ormore substituents selected from the group consisting of an aryl group, ahalogen atom and an alkoxyl group having from 1 to 6 carbon atoms; andin the cases of an aryl group as an aromatic group and an aryl group asa substituent on the fatty chain in the case of an aliphatic group, itmay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl group having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms),

an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl groups having from 1 to 6carbon atoms), or

an aralkyloxycarbonyl group (wherein the aralkyl group has a structurein which an aryl group is substituted on an alkyl group having from 1 to6 carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms);

R² represents

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms;

the aryl group moiety may have one or more substituents selected fromthe group consisting of a halogen atom, a nitro group, an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl groupshaving from 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6carbon atoms),

an acyl group (which may be either aliphatic or aromatic; in the case ofan aliphatic group, it has from 1 to 7 carbon atoms and may have one ormore substituents selected from the group consisting of an aryl group, ahalogen atom and an alkoxyl group having from 1 to 6 carbon atoms; andin the cases of an aryl group as an aromatic group and an aryl group asa substituent on the fatty chain in the case of an aliphatic group, itmay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl group having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms),

an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl groups having from 1 to 6carbon atoms), or

an aralkyloxycarbonyl group (wherein the aralkyl group has a structurein which an aryl group is substituted on an alkyl group having from 1 to6 carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms); and

R³ and R⁴ each independently represents an alkyl group having from 1 to6 carbon atoms (which may have one or more substituents selected fromthe group consisting of a halogen atom and an alkoxyl group having from1 to 6 carbon atoms), or

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms); or

R³ and R⁴ may together form a cyclic structure of from five-toeight-membered ring comprised of a polymethylene chain].

The present invention further relates to each of the following items.

A salt and a hydrate thereof, formed from a compound represented by aformula (IIIa) or formula (IIIb) and an acid as an optically activecompound;

the aforementioned salt and a hydrate thereof, wherein the acid as anoptically active compound is D-mandelic acid or L-mandelic acid;

the aforementioned salt and a hydrate thereof, wherein the acid as anoptically active compound is D-mandelic acid;

the aforementioned salt and a hydrate thereof, wherein the acid as anoptically active compound is L-mandelic acid;

the aforementioned salt and a hydrate thereof, wherein R³ and R⁴ are thesame group;

the aforementioned salt and a hydrate thereof, wherein R³ and R⁴ are amethyl group;

the aforementioned salt and a hydrate thereof, wherein R¹ is a hydrogenatom;

the aforementioned salt and a hydrate thereof, wherein R² is selectedfrom the group consisting of a tert-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, anacetyl group, a methoxyacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group and a benzoylgroup;

aforementioned salt and a hydrate thereof, wherein R² is abenzyloxycarbonyl group;

a method for producing a compound represented by a formula (Ia)

or formula (Ib):

[the above formulae,

R¹ represents

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),

an acyl group (which may be either aliphatic or aromatic; in the case ofan aliphatic group, it has from 1 to 7 carbon atoms and may have one ormore substituents selected from the group consisting of an aryl group, ahalogen atom and an alkoxyl group having from 1 to 6 carbon atoms; andin the cases of an aryl group as an aromatic group and an aryl group asa substituent on the fatty chain in the case of an aliphatic group, itmay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl group having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms),

an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl groups having from 1 to 6carbon atoms), or

an aralkyloxycarbonyl group (wherein the aralkyl group has a structurein which an aryl group is substituted on an alkyl group having from 1 to6 carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms); and

R² represents

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl groups having from 1 to 6carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),

an acyl group (which may be either aliphatic or aromatic; in the case ofan aliphatic group, it has from 1 to 7 carbon atoms and may have one ormore substituents selected from the group consisting of an aryl group, ahalogen atom and an alkoxyl group having from 1 to 6 carbon atoms; andin the cases of an aryl group as an aromatic group and an aryl group asa substituent on the fatty chain in the case of an aliphatic group, itmay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl group having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms),

an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl groups having from 1 to 6carbon atoms), or

an aralkyloxycarbonyl group (wherein the aralkyl group has a structurein which an aryl group is substituted on an alkyl group having from 1 to6 carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms)], which comprises the following steps 1, 2 and 3,

Step 1:

a step in which an enantiomer mixture of a compound represented byformula (I):

(in the formula, R¹ and R² are as defined in the foregoing, and thesubstituents R¹HN— and —CH₂OH on the pyrrolidine ring are in the cisconfiguration) is treated with a compound represented by formula (II):

[in the formula,

R³ and R⁴ each independently represents

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms), or

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms); orR³ and R⁴ may together form a cyclic structure of from five- toeight-membered ring comprised of a polymethylene chain] in the presenceof an acid as an optically active compound, thereby obtaining a saltformed from either of a compound represented by formula (IIIa):

or formula (IIIb):

and the optically active acid,

Step 2:

a step in which a free form is obtained by removing the acid from thesalt formed from the compound represented by formula (IIIa) or (IIIb)and the optically active acid, and

Step 3:

a step in which the compound represented by formula (Ia) or (Ib) isobtained by hydrolyzing the free form of the compound represented byformula (IIIa) or (IIIb);

the aforementioned production method, wherein the acid as an opticallyactive compound is D-mandelic acid or L-mandelic acid;

a method for producing a compound represented by formula (Ia)

[in the above formula,

R¹ represents

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),

an acyl group (which may be either aliphatic or aromatic; in the case ofan aliphatic group, it has from 1 to 7 carbon atoms and may have one ormore substituents selected from the group consisting of an aryl group, ahalogen atom and an alkoxyl group having from 1 to 6 carbon atoms; andin the cases of an aryl group as an aromatic group and an aryl group asa substituent on the fatty chain in the case of an aliphatic group, itmay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl group having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms),

an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl groups having from 1 to 6carbon atoms), or

an aralkyloxycarbonyl group (wherein the aralkyl group has a structurein which an aryl group is substituted on an alkyl group having from 1 to6 carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms); and

R² represents

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl groups having from 1 to 6carbon atoms and an alkoxyl groups having from 1 to 6 carbon atoms),

an acyl group (which may be either aliphatic or aromatic; in the case ofan aliphatic group, it has from 1 to 7 carbon atoms and may have one ormore substituents selected from the group consisting of an aryl group, ahalogen atom and an alkoxyl group having from 1 to 6 carbon atoms; andin the cases of an aryl group as an aromatic group and an aryl group asa substituent on the fatty chain in the case of an aliphatic group, itmay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl group having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms),

an alkyloxycarbonyl group having from 2 to 7 carbon atoms (the alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl groups having from 1 to 6carbon atoms), or

an aralkyloxycarbonyl group (wherein the aralkyl group has a structurein which an aryl group is substituted on an alkyl group having from 1 to6 carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms)], which comprises the following steps 1, 2 and 3,

Step 1:

a step in which an enantiomer mixture of a compound represented byformula (I):

(in the formula, R¹ and R² are as defined in the foregoing, and thesubstituents R¹HN— and —CH₂OH on the pyrrolidine ring are in the cisconfiguration) is treated with a compound represented by formula (II):

[in the formula,

R³ and R⁴ each independently represents

an alkyl group having from 1 to 6 carbon atoms (which may have one ormore substituents selected from the group consisting of a halogen atomand an alkoxyl group having from 1 to 6 carbon atoms), or

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms); orR³ and R⁴ may together form a cyclic structure of from five- toeight-membered ring comprised of a polymethylene chain] in the presenceof an acid as an optically active compound, thereby obtaining a saltformed from a compound represented by a formula (IIIa):

and the optically active acid,

Step 2:

a step in which a free form is obtained by removing the acid from thesalt formed from the compound represented by formula (IIIa) and theoptically active acid, and

Step 3:

a step in which the compound represented by formula (Ia) is obtained byhydrolyzing the free form of the compound represented by formula (IIIa);

the aforementioned production method, wherein the acid as an opticallyactive compound is D-mandelic acid;

the aforementioned production method, wherein R³ and R⁴ are the samegroup;

the aforementioned production method, wherein R³ and R⁴ are methylgroup;

the aforementioned production method, wherein R¹ is a hydrogen atom;

the aforementioned production method, wherein R² is selected from thegroup consisting of a tert-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, anacetyl group, a methoxyacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group and a benzoylgroup; the aforementioned production method, wherein R² is abenzyloxycarbonyl group;

and so on.

MODE FOR CARRYING OUT THE INVENTION

The compound of the invention represented by formula (I) is described.

The substituent R¹ is a hydrogen atom, an alkyl group having from 1 to 6carbon atoms, an aralkyl group, an acyl group, an alkyloxycarbonyl grouphaving from 2 to 7 carbon atoms or an aralkyloxycarbonyl group. When R¹is a group other than hydrogen atom, which has such a property that itcan take a role as a protecting group and can be easily removed, such asbenzyl group or the like, it is useful as a material compound that canbe further converted into various compounds.

The alkyl group may be in the form of a straight chain or a branchedchain or in a cyclic form. Also, this alkyl group may have one or moresubstituents selected from the group consisting of a halogen atom and analkoxyl group having from 1 to 6 carbon atoms. Their substitutingposition is not particularly limited, but on the terminal carbon atom isdesirable. As the halogen atom, fluorine atom or chlorine atom isdesirable. The substitution number of halogen atoms may be one or more,but it may become a perfluoro substitution in the case of fluorine atom.The alkyl moiety of the alkoxyl group may also be in the form of astraight chain or a branched chain or in a cyclic form. As the alkylgroup, a methyl group, an ethyl group, a propyl group, a butyl group, atrifluoromethyl group, a methoxymethyl group, a methoxyethyl group andthe like are desirable.

The aralkyl group may have a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms. The arylgroup moiety thereof may have one or more substituents selected from thegroup consisting of a halogen atom, a nitro group, an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms. The alkyl group moiety may also have one or more substituentsselected from the group consisting of alkyl groups having from 1 to 6carbon atoms and alkoxyl groups having from 1 to 6 carbon atoms. Thesealkyl groups and alkyl moieties of the alkoxyl groups may be in the formof a straight chain or a branched chain or in a cyclic form. As thearalkyl group, a α-phenylethyl group, a benzyl group, a nitrobenzylgroup, a trityl group, a toluyl group and the like are desirable.

The acyl group may be either aliphatic or aromatic. In the case of analiphatic acyl group, it has from 2 to 7 carbon atoms and is either instraight chain or branched chain form. In addition, the fatty chainmoiety may have one or more substituents selected from the groupconsisting of an aryl group, a halogen atom and an alkoxyl group havingfrom 1 to 6 carbon atoms. Their substituting position is notparticularly limited, but on the terminal carbon atom is desirable. Asthe halogen atom, chlorine atom or fluorine atom is desirable. Thesubstitution number of halogen atoms may be one or more, and it maybecome a perfluoro substitution in the case of fluorine atom.

The aryl group as the substituent of aromatic acyl groups and of thefatty chain moiety of aliphatic acyl groups may have one or moresubstituents selected from the group consisting of a halogen atom, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms. The alkyl moiety of thesealkyl groups and alkoxyl groups may be in the form of a straight chainor a branched chain or in a cyclic form. As the acyl group, an acetylgroup, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetylgroup, a pivaloyl group, a formyl group, a benzoyl group, anitrophenylacetyl group and the like are desirable.

The alkyloxycarbonyl group may have from 2 to 7 carbon atoms. Its alkylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl group having from 1 to 6carbon atoms. Fluorine atom or chlorine atom is desirable as the halogenatom, and the alkyl moiety of alkoxyl groups may be in the form of astraight chain or a branched chain or in a cyclic form. As thealkyloxycarbonyl group, a methoxycarbonyl group, a tert-butoxycarbonylgroup, a 2,2,2-trichloroethoxycarbonyl group and the like are desirable.

Regarding the aralkyloxycarbonyl group, its aralkyl group moiety may beconsidered in the same manner as the aforementioned aralkyl group. Asthe aralkyloxycarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group andthe like are desirable.

The substituent R² is a hydrogen atom, an alkyl group having from 1 to 6carbon atoms, an aralkyl group, an acyl group, an alkyloxycarbonyl grouphaving from 2 to 7 carbon atoms or an aralkyloxycarbonyl group, and theycan be considered in the same manner as the substituent R¹. Regardingthe substituent R², preferred are a methyl group, an ethyl group, apropyl group, a butyl group, a trifluoromethyl group, a methoxymethylgroup, a methoxyethyl group and the like as the alkyl group; aα-phenylethyl group, a benzyl group, a nitrobenzyl group, a tritylgroup, a toluyl group and the like as the aralkyl group; an acetylgroup, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetylgroup, a pivaloyl group, a formyl group, a benzoyl group,nitrophenylacetyl group and the like as the acyl group; amethoxycarbonyl group, a tert-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group and the like as the alkyloxycarbonylgroup; and a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonylgroup, a p-nitrobenzyloxycarbonyl group and the like as thearalkyloxycarbonyl group.

The compound represented by formula (I) can be produced by the methodshown as reference examples in this specification or, alternatively, canbe produced by applying to this method certain modifications which canbe generally considered by those skilled in the art.

Next, the compound represented by formula (II) is described.

In this case, the substituents R³and R⁴ each independently represents analkyl group having from 1 to 6 carbon atoms or an aralkyl group, or R³and R⁴ may together form a cyclic structure of from five- toeight-membered ring comprised of a polymethylene chain.

These alkyl groups and aralkyl groups can be considered in the samemanner as the substituent R¹. Regarding the substituents R³ and R⁴,preferred are a methyl group, an ethyl group, a propyl group, a butylgroup, a trifluoromethyl group, a methoxymethyl group, a methoxyethylgroup and the like as the alkyl group; a phenyl group, a dimethoxyphenylgroup, a p-methoxyphenyl group and the like as the aryl group; and aα-phenylethyl group, a benzyl group, a nitrobenzyl group, a tritylgroup, a toluyl group and the like as the aralkyl group. Also, R³ and R⁴may together form a cyclic structure of from five- to eight-memberedring (including the carbon atom to which R³ and R⁴ are bound) comprisedof a polymethylene chain. When a cyclic structure is formed, size of thering is preferably a five-membered ring or six-membered ring. This ringmay be further substituted by a substituent, and an alkyl group isdesirable as the substituent on the cyclic structure. When the cyclicstructure has a substituent in this manner, it is desirable to introducethe substituent to effect enantiomorph. That is, it is desirable thatthe oxazine ring formed by the reaction of the compound of formula (II)with the compound of formula (I) does not generate new asymmetriccenter.

Since it is desirable that a new asymmetric center is not generated, R³and R⁴ are preferably the same group. Acetone is particularly desirableas the ketone compound represented formula (II).

In the reaction for forming a condensed oxazine compound, it may becarried out using a solvent, and because of the presence of a ketonecompound represented by formula (II), the examples of the solvent suitedfor this reaction include toluene, xylene and the like hydrocarbonsolvents; diisopropyl ether, diethyl ether, tetrahydrofuran and the likeether solvents; chloroform, dichloromethane and the like halogenatedhydrocarbon solvents; and ethyl acetate and the like esters. These maybe used as a mixed solvent. On the other hand, a ketone compoundrepresented by formula (II) can also be used by itself as a solvent.Practically, it is desirable to use a ketone compound represented byformula (II) serving also as a solvent. Also from such a point of view,acetone is desirable as the compound (II).

Regarding the amount of the solvent, a salt of the oxazine compound canbe crystallized using approximately from 3 to 100 times, more preferablyfrom about 6 to 20 times, particularly preferably about 10 times, of thesolvent based on the compound represented by formula (I).

At the time of the reaction, mixing ratio of the compound represented byformula (I) and the acid as an optically active compound may beapproximately from 0.1 to 3 moles, more preferably from about 0.5 to 2moles, particularly preferably from about 1 to 1.25 moles, of theoptically active acid based on 1 mole of the former compound. As amatter of course, the acid as an optically active compound is a puresubstance (consisting of a single isomer) (the term “pure” as usedherein means a chemically pure degree).

Crystallization of a salt of the condensed oxazine compound can becarried out at a temperature of from the melting point to boiling pointof the solvent to be used, but is preferably from about −40 to 20° C.,particularly preferably from −20 to 0° C.

The crystallization time may be 30 minutes or more, but preferably fromabout 20 to 80 hours, particularly preferably from about 40 to 60 hours.

Also, the thus precipitated salt of the condensed oxazine compound withoptically active acid can be further purified by recrystallizing it orstirring it under a suspended condition in a solvent after collecting itby filtration. The solvent in this case is preferably acetone, but theaforementioned solvents can be optionally used. Also, there-purification by recrystallization or stirring under a suspendedcondition in a solvent can be carried out between the melting point andboiling point of the solvent to be used, preferably at about −20 to 0°C.

The thus obtained salt of the condensed oxazine compound as an opticallyactive compound represented by formula (III) with the acid as anoptically active compound may sometimes contain the solvent used in theprecipitation of salt and re-purification as a crystal solvent oradhered solvent. In addition, there will be a case in which it containscrystal water or adhered water.

The present invention also contemplates providing a method for obtaininga pure enantiomer compound represented by the formula (Ia) or (Ib), inwhich a salt of the cyclic compound as an optically active compoundrepresented by formula (III) with the acid as an optically activecompound is subjected to salt exchange by a base in an organic solventand then to hydrolysis via the cyclic compound as a free opticallyactive compound.

The base to be used in the salt exchange is an aqueous solution ofhydroxide of sodium, potassium or the like alkali metal ortriethylamine, pyridine or the like organic base, and an aqueoussolution of hydroxide of sodium, potassium or the like alkali metal ispreferable.

The solvent is toluene or the like hydrocarbon solvent, diisopropylether, diethyl ether or the like ether solvent, chloroform,dichloromethane or the like chlorine based solvent, ethyl acetate or amixed solvent thereof, of which ethyl acetate is particularly desirable.

In this case, amount of the solvent is approximately from 3 to 50 times,preferably from about 5 to 20 times, particularly preferably from about5 to 10 times, of the compound represented by formula (III).

Mixing ratio of the compound represented by formula (III) and the baseis approximately from 1 to 3 moles, preferably from about 1 to 1.5moles, particularly preferably from about 1 to 1.1 moles, of the basebased on 1 mole of the compound represented by formula (III).

The reaction can be carried out at a temperature of from the meltingpoint to boiling point of the solvent to be used, but is preferably fromabout 0 to 80° C., particularly preferably from 20 to 60° C.

The reaction time may be 30 minutes or more, but is preferably fromabout 1 to 12 hours, particularly preferably from about 3 to 6 hours.

In many cases, it is difficult to isolate the cyclic compoundrepresented by formula (III), because the reaction partially proceeds tothe optically active aminoalcohol derivative represented by the formula(I).

Hydrolysis of the cyclic compound represented by formula (III) can becarried out under either an acidic or basic condition.

In the case of an acidic condition, hydrochloric acid, sulfuric acid orthe like inorganic acid or acetic acid, trifluoromethanesulfonic acid orthe like organic acid may be used.

In the case of a basic condition, the base to be used is an aqueoussolution of hydroxide of sodium, potassium or the like alkali metal ortriethylamine, pyridine or the like organic base.

Among these conditions, preferred is an acidic condition, andhydrochloric acid aqueous solution is particularly desirable.

In the case of the acidic condition, the reaction can be carried out ata temperature of from the melting point to boiling point of the solventto be used, but is preferably from about 0 to 30° C., particularlypreferably from about 10 to 20° C.

In the case of the acidic condition, the reaction time may be 30 minutesor more, but is preferably from about 1 to 24 hours, particularlypreferably from about 6 to 12 hours.

The method of the present invention can be applied to any compound inwhich amino group and hydroxyl group are substituted on such positionsthat a 1-oxa-3-aza cyclic compound of five-membered ring or six-memberedring can be formed by incorporating carbon atom of the ketone compound,so that its application is not limited to the compound of formula (I).The present inventors have considered that a or y-aminoalcohol compoundis suitable as a compound to which the method of the invention can beapplied. A compound represented by the following formula (A) can becited as its illustrative example.

[In the formula, R^(a) represents a hydrogen atom, an alkyl group havingfrom 1 to 6 carbon atoms (which may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms),

an aralkyl group (having a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group,

an alkyl group having from 1 to 6 carbon atoms and an alkoxyl groupshaving from 1 to 6 carbon atoms; and the alkyl group moiety may have oneor more substituents selected from the group consisting of an alkylgroup having from 1 to 6 carbon atoms and an alkoxyl group having from 1to 6 carbon atoms), an acyl group (which may be either aliphatic oraromatic; in the case of an aliphatic group, it has from 1 to 7 carbonatoms and may have one or more substituents selected from the groupconsisting of an aryl group, a halogen atom and an alkoxyl group havingfrom 1 to 6 carbon atoms; and in the cases of an aryl group as anaromatic group and an aryl group as a substituent on the fatty chain inthe case of an aliphatic group, it may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl groups havingfrom 1 to 6 carbon atoms), an alkyloxycarbonyl group having from 2 to 7carbon atoms (the alkyl group moiety may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms), or an aralkyloxycarbonyl group(wherein the aralkyl group has a structure in which an aryl group issubstituted on an alkyl group having from 1 to 6 carbon atoms; the arylgroup moiety may have one or more substituents selected from the groupconsisting of a halogen atom, a nitro group, an alkyl group having from1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms; and the alkyl group moiety may have one or more substituentsselected from the group consisting of an alkyl group having from 1 to 6carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms),

R^(b), R^(c), R^(d) and R^(e) each independently represents a hydrogenatom, an alkyl group having from 1 to 6 carbon atoms (which may have oneor more substituents selected from the group consisting of a halogenatom and an alkoxyl group having from 1 to 6 carbon atoms), or anaralkyl group (having a structure in which an aryl group is substitutedon an alkyl group having from 1 to 6 carbon atoms; the aryl group moietymay have one or more substituents selected from the group consisting ofa halogen atom, a nitro group, an alkyl groups having from 1 to 6 carbonatoms and an alkoxyl group having from 1 to 6 carbon atoms; and thealkyl group moiety may have one or more substituents selected from thegroup consisting of an alkyl group having from 1 to 6 carbon atoms andan alkoxyl group having from 1 to 6 carbon atoms), with the proviso that

R^(b) and R^(c) are not the same and/or

R^(d) and R^(e) are not the same, and

n¹ is 1 or 0.]

More preferred compound is a compound represented by the followingformula (B) in which the substituents R^(c) and R^(d) in theaforementioned compound together form a cyclic structure. The presentinventors have considered that this compound represented by the formula(B) gives a more rigid salt having good crystallinity when the salt isformed from a cyclic compound and an acid.

[In the formula,

R^(a), R^(b), R^(e) and n¹ are as defined in the foregoing,

Y¹ represents a methylene group (>CH₂), a carbonyl group (>C═O) or astructure >CHR^(f),

Y² represents a methylene group (>CH₂), a carbonyl group (>C═O) or astructure >CHR^(g),

Z represents a methylene group (>CH₂), a carbonyl group (>C═O), astructure >CHR^(h) or a structure >NR^(i),

R^(f), R^(g) and R^(h) each independently represents an alkyl grouphaving from 1 to 6 carbon atoms (which may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms), or an aralkyl group (having astructure in which an aryl group is substituted on an alkyl group havingfrom 1 to 6 carbon atoms; the aryl group moiety may have one or moresubstituents selected from the group consisting of a halogen atom, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 6 carbon atoms and analkoxyl groups having from 1 to 6 carbon atoms),

R^(i) represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (which may have one or more substituents selected from thegroup consisting of a halogen atom and an alkoxyl group having from 1 to6 carbon atoms), an aralkyl group (having a structure in which an arylgroup is substituted on an alkyl group having from 1 to 6 carbon atoms;the aryl group moiety may have one or more substituents selected fromthe group consisting of a halogen atom, a nitro group, an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms), an acyl group (which may be either aliphatic or aromatic; in thecase of an aliphatic group, it has from 1 to 7 carbon atoms and may haveone or more substituents selected from the group consisting of an arylgroup, a halogen atom and an alkoxyl groups having from 1 to 6 carbonatoms; and in the cases of an aryl group as an aromatic group and anaryl group as a substituent on the fatty chain in the case of analiphatic group, it may have one or more substituents selected from thegroup consisting of a halogen atom, a nitro group, an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms), an alkyloxycarbonyl group having from 2 to 7 carbon atoms (thealkyl group moiety may have one or more substituents selected from thegroup consisting of a halogen atom and an alkoxyl groups having from 1to 6 carbon atoms), or an aralkyloxycarbonyl group (wherein the aralkylgroup has a structure in which an aryl group is substituted on an alkylgroup having from 1 to 6 carbon atoms; the aryl group moiety may haveone or more substituents selected from the group consisting of a halogenatom, a nitro group, an alkyl group having from 1 to 6 carbon atoms andan alkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms), and each of n² and n³ isindependently an integer of 8 or less, with the proviso that the totalof both cases is 3 or more and 8 or less (3≦(n²+n³)≦8) (wherein thesymbol “>” means bonding of an atom to its adjacent atom).]

Each of the substituents of compounds represented by formulae (A) and(B) can be considered in the same manner as the already describedcorresponding substituent.

Regarding the compound represented by formula (B), isomers are generatedbased on the amino group moiety and hydroxyl group moiety. That is, itexists in two cis and trans forms, and each of them exists in two isomerforms having enantiomorphic relationship. Though these isomers can beseparated by the method of the invention, it is desirable to use amixture of only cis form enantiomers or a mixture of only trans formenantiomers in carrying out the separation. These requirements can beapplied in the same manner to the compound of formula (A).

An acidic condition is necessary in forming a 1-oxa-3-aza cycliccompound with the ketone compound, and the acid as an optically activecompound to be used in the method of the invention takes a role inproviding such an acidic condition. In addition, since this acid isoptically active and the acid to be used in the practical reaction iscomprised of only a single enantiomer, optical resolution is attained byforming a salt with one of the enantiomers of the compound of formula(A) or formula (B).

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention is described further illustratively based onExamples and Reference Examples, though the invention is not limitedthereto.

EXAMPLE 11S,6S)-8-Benzyloxycarbonyl-4,4-dimethyl-5,8-diaza-3-oxabicyclo[4.3.0]nonaneD-Mandelate

[Cbz: Benzyloxycarbonyl]

A mixture of3,4-cis-3-amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine (racemiccompound; 3.00 g) and D-mandelic acid (1.83 g) was dissolved in acetone(30 ml) at room temperature. After the dissolution, the resultingsolution was stirred at −20° C. for 48 hours and then the thusprecipitated salt was collected by filtration and dried at roomtemperature under a reduced pressure, thereby obtaining 2.26 g of thetitle compound.

Elemental analysis: C₂₄H₃₀N₂O₆; Calcd: C, 64.27; H, 6.89; N, 6.25;Found: C, 64.37; H, 6.76; N, 6.20; Melting point: 77-79° C.; MASS:m/e=291 (FABMS); ¹H-NMR (DMSO-d₆) δ (ppm): 1.20 (3 H, s, 3-CHa), 1.30 (3H, s, 3-CHb), (2.08 (s, acetone formed by decomposition of the titlecompound)), 3.15-4.00 (8 H, m, H1, H5a, H5b, H6, H7a, H7b), 4.90 (1 H,s, methine proton of D-mandelic acid), 5.06 (2 H, s, 8-NCO₂CH₂Ph),7.25-7.42 (10 H, m, 8-NCO₂CH₂Ph, phenyl proton of D-mandelic acid).

(It was confirmed by NMR that the title compound was decomposed withpassage of time in DMSO-d₆ to partially form3-amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine and acetone.Assignment of the spectrum was described as the peak originated from thetitle compound.)

Optical purity: 95.6% ee (measured by inducing the salt into3-(N-tert-butoxycarbonyl)amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine)

EXAMPLE 2Spiro[(1S,6S)-5,8-diaza-8-benzyloxycarbonyl-3-oxabicyclo[4.3.0]nonane-4,1′-cyclohexane]D-Mandelate

A mixture of3,4-cis-3-amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine (racemiccompound; 100 mg) and D-mandelic acid (61 mg) was dissolved incyclohexanone (1 ml) at room temperature. After the dissolution, theresulting solution was stirred at 0° C. for 16 hours and then the thusprecipitated salt was collected by filtration and washed withdiisopropyl ether. This was dried at room temperature under a reducedpressure to obtain 57.8 mg of the title compound.

Elemental analysis: C₂₇H₃₄N₂O₆; Calcd: C, 67.20; H, 7.10; N, 5.80;Found: C, 67.27; H, 7.21; N, 5.59; Melting point: 144-147° C.; MASS:m/e=331 (FABMS); ¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.97 (10 H, s,3-cyclohexyl), 3.11-3.97 (8 H, overlapped the signals of H1, H5a, H5b,H6, H7a, H7b), 4.95 (1 H, s, methine proton of D-mandelic acid), 5.01 (2H, s, 8-NCO₂CH₂Ph), 7.24-7.42 (10 H, m, 8-NCO₂CH₂Ph, phenyl proton ofD-mandelic acid).

Optical purity: 97.5% ee (measured by inducing the salt into3-(N-tert-butoxycarbonyl)amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine)

EXAMPLE 3(1R,6R)-8-Benzyloxycarbonyl-4,4-dimethyl-5,8-diaza-3-oxabicyclo[4.3.0]nonaneL-Mandelate

A mixture of3,4-cis-3-amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine (racemiccompound; 800 mg) and L-mandelic acid (488 mg) was dissolved in acetone(8 ml) at room temperature. After the dissolution, the resultingsolution was stirred at −20° C. for 54 hours. The thus precipitated saltwas collected by filtration and dried at room temperature under areduced pressure to obtain 448 mg of the title compound.

Melting point: 86-87° C.

Optical purity: 95.8% ee (measured by inducing the salt to3-(N-tert-butoxycarbonyl)amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine)

EXAMPLE 4 (3S,4S)-3-Amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine

A 670 g portion of(1S,6S)-2,8-diaza-3,3-dimethyl-4-oxa-8-benzyloxycarbonylbicyclo[4.3.0]nonaneD-mandelate (optical purity: 97.8% ee) was mixed with 1 N hydrochloricacid aqueous solution (6,700 ml) and ethyl acetate (6,700 ml) andstirred to extract mandelic acid into the organic layer, the organiclayer was removed and then the water layer was stirred at roomtemperature for 6 hours. After completion of the reaction, the aqueoussolution was adjusted to strongly basic level with 5 N sodium hydroxideaqueous solution and extracted with chloroform (12,000 ml) three times(4,000 ml×3) and then the extracts were concentrated to dryness, therebyobtaining 373 g of the title compound.

Optical purity: 97.8% ee (measured by inducing the salt to3-(N-tert-butoxycarbonyl)amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine)

REFERENCE EXAMPLE 11-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine

Ethyl acrylate (65.01 ml, 600.0 mmol) was added to a toluene (1,200 ml)solution containing N-benzyloxycarbonylglycine ethyl ester (156.3 g,600.0 mmol) and then, under ice-cooling, sodium hydride (60% oil; 26.40g, 660.0 mmol) was added thereto. After 10 minutes of stirring at thesame temperature, the ice bath was taken off, and the mixture wasstirred at room temperature for 20 minutes and then at 50° C. for 3hours. After completion of the reaction, and under ice-cooling, thereaction solution was adjusted to about pH 3 by adding 10% citric acidaqueous solution and mixed with ethyl acetate, and the mixture wasshaken and then subjected to separation of layers. The organic layer wasseparated and washed with saturated brine, and the water layer wasfurther extracted with ethyl acetate. The organic layers were dried overanhydrous sodium sulfate and then filtered, and the solvent wasevaporated under a reduced pressure to obtain 196.7 g (600.0 mmol,quantitative) of the title compound.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.22-1.32 (3 H, m), 3.93-4.05 (1 H, m),4.05-4.31 (5 H, m), 5.13-5.23 (2 H, m), 7.28-7.40 (5 H, m).

REFERENCE EXAMPLE 21-Benzyloxycarbonyl-4-ethoxycarbonyl-3-methoxyiminopyrrolidine

1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine (196.7 g, 600.0mmol) was dissolved in pyridine (700 ml) and mixed withO-methylhydroxylamine hydrochloride (76.55 g, 916.5 mmol) underice-cooling, and the mixture was stirred at the same temperature for 10minutes and then at room temperature for 5 hours. Pyridine wasevaporated under a reduced pressure, the residue was mixed with 1 Nhydrochloric acid and ethyl acetate and then the mixture was shaken andsubjected to separation of layers. The organic layer was washed withsaturated brine, and the water layer was further extracted with ethylacetate. The organic layers were dried over anhydrous sodium sulfate andfiltered, the solvent was evaporated under a reduced pressure and thenthe residue was purified by a silica gel column chromatography(n-hexane:ethyl acetate=1:1) to obtain 187.5 g (589.1 mmol, 98.2%) ofthe title compound.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.15-1.32 (3 H, m), 3.55-4.05 (5 H, m),4.05-4.25 (4 H, m), 5.09-5.20 (2 H, m), 7.28-7.40 (5 H, m).

REFERENCE EXAMPLE 33,4-cis-1-Benzyloxycarbonyl-3-tert-butoxycarbonylamino-4-hydroxymethylpyrrolidine

1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-methoxyiminopyrrolidine (248.8 g,550.0 mmol) was dissolved in anhydrous tetrahydrofuran (1,000 ml), atetrahydrofuran solution of 1 M borane-tetrahydrofuran complex (2.75 l,2.75 mol) was added dropwise to the above solution which was stirred at−78° C., and the mixture was stirred at the same temperature for 1.5hours, under ice-cooling for 2 hours and then at room temperature for 12hours. Under ice-cooling, water was added to the reaction solution untilgeneration of gas stopped, and the solution was mixed with potassiumcarbonate (60.8 g) and stirred at room temperature for 1 hour. Next, thereaction solution was mixed with di-tert-butyl bicarbonate (144.0 g,660.0 mmol) under ice-cooling and then stirred at room temperature for16 hours. The reaction solution was mixed with water and ethyl acetateand shaken, and then the organic layer was separated. The organic layerwas washed with saturated brine and then dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under a reducedpressure. The thus obtained residue was crystallized. A portion of thethus precipitated crystals was purified by a silica gel columnchromatography (n-hexane:ethyl acetate=2:1) and combined with theun-purified crystals to obtain 121.99 g (348.1 mmol, 63.3%) of the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 1.46 (9 H, s), 2.52-2.56 (1 H, m),2.88-2.96 (1 H, m), 3.44-3.92 (6 H, m), 4.28 (1 H, br), 4.76-4.81 (1 H,m), 5.10 (1 H, d, J=13.0 Hz), 5.14 (1 H, d, J=13.0 Hz), 7.29-7.37 (5 H,m)

REFERENCE EXAMPLE 43,4-cis-3-Amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine

3-(N-tert-Butoxycarbonyl)amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine(10.0 g, 28.54 mmol) was dissolved in 1 N hydrochloric acid/ethanol (150ml) and stirred at 45° C. for 15 hours. The reaction solution wasevaporated under a reduced pressure, and the residue was mixed withdichloromethane and 1 N sodium hydroxide and shaken and then subjectedto separation of layers. The organic layer was extracted and then theextract was concentrated to dryness to obtain 7.13 g (28.49 mmol,quantitative) of the title compound.

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 2.29-2.41 (1 H, m, H4), 3.25-3.69 (5 H,m, H2a, H2b, H3, H5a, H5b), 3.80 (2 H, d, 4-CH₂OH), 5.13 (2 H, s,1-NCO₂CH₂Ph), 7.30-7.37 (5 H, m, 1-NCO₂CH₂Ph) MASS: m/e=251 (FABMS).

What is claimed is:
 1. A compound represented by the following formula(IIIa):

or formula (IIIb):

wherein R¹ represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (which may have one or more substituents selected from thegroup consisting of a halogen atom and an alkoxyl group having from 1 to6 carbon atoms), an aralkyl group (having a structure in which an arylgroup is substituted on an alkyl group having from 1 to 6 carbon atoms;the aryl group moiety may have one or more substituents selected fromthe group consisting of a halogen atom, a nitro group, an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6 carbonatoms), an acyl group (which may be either aliphatic or aromatic; in thecase of an aliphatic group, it has from 1 to 7 carbon atoms and may haveone or more substituents selected from the group consisting of an arylgroup, a halogen atom and an alkoxyl group having from 1 to 6 carbonatoms, wherein said aryl group may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkyl group havingfrom 1 to 6 carbon atoms; and in the case of an aromatic group, thearomatic moiety is an aryl group, wherein said aryl group may have oneor more substituents selected from the group consisting of a halogenatom, a nitro group, an alkyl group having from 1 to 6 carbon atoms andan alkoxyl group having from 1 to 6 carbon atoms), an alkyloxycarbonylgroup having from 2 to 7 carbon atoms (the alkyl group moiety may haveone or more substituents selected from the group consisting of a halogenatom and an alkoxyl groups having from 1 to 6 carbon atoms), or anaralkyloxycarbonyl group (wherein the aralkyl group has a structure inwhich an aryl group is substituted on an alkyl group having from 1 to 6carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms); R² represents a hydrogen atom, an alkyl group having from1 to 6 carbon atoms (which may have one or more substituents selectedfrom the group consisting of a halogen atom and an alkoxyl group havingfrom 1 to 6 carbon atoms), an aralkyl group (having a structure in whichan aryl group is substituted on an alkyl group having from 1 to 6 carbonatoms; the aryl group moiety may have one or more substituents selectedfrom the group consisting of a halogen atom, a nitro group, an alkylgroup having from 1 to 6 carbon atoms and an alkoxyl group having from 1to 6 carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl groupshaving from 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6carbon atoms), an acyl group (which may be either aliphatic or aromatic;in the case of an aliphatic group, it has from 1 to 7 carbon atoms andmay have one or more substituents selected from the group consisting ofan aryl group, a halogen atom and an alkoxyl group having from 1 to 6carbon atoms; and in the cases of an aryl group as an aromatic group andan aryl group as a substituent on the fatty chain in the case of analiphatic group, it may have one or more substituents selected from thegroup consisting of a halogen atom, a nitro group, an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms), an alkyloxycarbonyl group having from 2 to 7 carbon atoms (thealkyl group moiety may have one or more substituents selected from thegroup consisting of a halogen atom and an alkoxyl groups having from 1to 6 carbon atoms), or an aralkyloxycarbonyl group (wherein the aralkylgroup has a structure in which an aryl group is substituted on an alkylgroup having from 1 to 6 carbon atoms; the aryl group moiety may haveone or more substituents selected from the group consisting of a halogenatom, a nitro group, an alkyl group having from 1 to 6 carbon atoms andan alkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms); and R³ and R⁴ eachindependently represents an alkyl group having from 1 to 6 carbon atoms(which may have one or more substituents selected from the groupconsisting of a halogen atom and an alkoxyl group having from 1 to 6carbon atoms), or an aralkyl group (having a structure in which an arylgroup is substituted on an alkyl group having from 1 to 6 carbon atoms;the aryl group moiety may have one or more substituents selected fromthe group consisting of a halogen atom, a nitro group, an alkyl grouphaving from 1 to 6 carbon atoms and alkoxyl group having from 1 to 6carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 6 carbon atoms and a alkoxyl group having from 1 to 6 carbonatoms); or R³ and R⁴ may together form a cyclic structure of from five-to eight-membered ring consisting of a polymethylene chain.
 2. A saltand a hydrate thereof, formed from a compound represented by the formula(IIIa) or formula (IIIb) according to claim 1 and an acid as anoptically active compound.
 3. The salt and a hydrate thereof accordingto claim 2, wherein the acid as an optically active compound isD-mandelic acid or L-mandelic acid.
 4. The salt and a hydrate thereofaccording to claim 2, wherein the acid as an optically active compoundis D-mandelic acid.
 5. The salt and a hydrate thereof according to claim2, wherein the acid as an optically active compound is L-mandelic acid.6. The salt and a hydrate thereof according to any one of claims 2 to 5,wherein R³ and R⁴ are the same group.
 7. The salt and a hydrate thereofaccording to any one of claims 2 to 5, wherein R³ and R⁴ are a methylgroup.
 8. The salt and a hydrate thereof according to any one of claims2 to 7, wherein R¹ is a hydrogen atom.
 9. The salt and a hydrate thereofaccording to any one of claims 2 to 8, wherein R² is selected from thegroup consisting of a tert-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, anacetyl group, a methoxyacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group and a benzoylgroup.
 10. The salt and a hydrate thereof according to any one of claims2 to 8, wherein R² is a benzyloxycarbonyl group.
 11. A method forproducing a compound represented by a formula (Ia):

or formula (Ib):

wherein R¹ represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (which may have one or more substituents selected from thegroup consisting of a halogen atom and an alkoxyl group having from 1 to6 carbon atoms), an aralkyl group (having a structure in which an arylgroup is substituted on an alkyl group having from 1 to 6 carbon atoms;the aryl group moiety may have one or more substituents selected fromthe group consisting of a halogen atom, a nitro group, an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6 carbonatoms),an acyl group (which may be either aliphatic or aromatic; in thecase of an aliphatic group, it has from 1 to 7 carbon atoms and may haveone or more substituents selected from the group consisting of an arylgroup, a halogen atom and an alkoxyl group having from 1 to 6 carbonatoms, wherein said aryl group may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and in the case of an aromatic group, thearomatic moiety is an aryl group, wherein said aryl group may have oneor more substituents selected from the group consisting of a halogenatom, a nitro group, an alkyl group having from 1 to 6 carbon atoms andan alkoxyl group having from 1 to 6 carbon atoms), an alkyloxycarbonylgroup having from 2 to 7 carbon atoms (the alkyl group moiety may haveone or more substituents selected from the group consisting of a halogenatom and an alkoxyl groups having from 1 to 6 carbon atoms), or anaralkyloxycarbonyl group (wherein the aralkyl group has a structure inwhich an aryl group is substituted on an alkyl group having from 1 to 6carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms); and R² represents a hydrogen atom, an alkyl group havingfrom 1 to 6 carbon atoms (which may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms), an aralkyl group (having astructure in which an aryl group is substituted on an alkyl group havingfrom 1 to 6 carbon atoms; the aryl group moiety may have one or moresubstituents selected from the group consisting of a halogen atom, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl groups having from 1 to 6 carbon atoms and analkoxyl groups having from 1 to 6 carbon atoms), an acyl group (whichmay be either aliphatic or aromatic; in the case of an aliphatic group,it has from 1 to 7 carbon atoms and may have one or more substituentsselected from the group consisting of an aryl group, a halogen atom andan alkoxyl group having from 1 to 6 carbon atoms; and in the cases of anaryl group as an aromatic group and an aryl group as a substituent onthe fatty chain in the case of an aliphatic group, it may have one ormore substituents selected from the group consisting of a halogen atom,a nitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms), an alkyloxycarbonylgroup having from 2 to 7 carbon atoms (the alkyl group moiety may haveone or more substituents selected from the group consisting of a halogenatom and an alkoxyl group having from 1 to 6 carbon atoms), or anaralkyloxycarbonyl group (wherein the aralkyl group has a structure inwhich an aryl group is substituted on an alkyl group having from 1 to 6carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 atoms and an alkoxyl group having from 1to 6 carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbonatoms), which comprises the following steps 1, 2 and 3, Step 1: a stepwhich an enantiomer mixture of a compound represented by a formula (I):

wherein R¹ and R² are as defined in the foregoing, and the substituentsR¹HN— and —CH₂OH on the pyrrolidine ring are in the cis configuration,is treated with a compound represented by formula (II):

wherein R³ and R⁴ each independently represents an alkyl group havingfrom 1 to 6 carbon atoms (which may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms), or an aralkyl group (having astructure in which an aryl group is substituted on an alkyl group havingfrom 1 to 6 carbon atoms; the aryl group moiety may have one or moresubstituents selected from the group consisting of a halogen atom, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms); or R³ and R⁴ maytogether form a cyclic structure of from five- to eight-membered ringcomprised of a polymethylene chain in the presence of an acid as anoptically active compound, thereby obtaining a salt formed from eitherof a compound represented by formula (IIIa):

or a formula (IIIb):

and the optically active acid, Step 2: a step in which a free form isobtained by removing the acid from the salt formed from the compoundrepresented by formula (IIIa) or (IIIb) and the optically active acid,and Step 3: a step in which the compound represented by formula (Ia) or(Ib) is obtained by hydrolyzing free form of the compound represented bythe formula (IIIa) or (IIIb).
 12. The production method according toclaim 11, wherein the acid as an optically active compound is D-mandelicacid or L-mandelic acid.
 13. A method for producing a compoundrepresented by a formula (Ia):

wherein R¹ represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (which may have one or more substituents selected from thegroup consisting of a halogen atom and an alkoxyl group having from 1 to6 carbon atoms), an aralkyl group (having a structure in which an arylgroup is substituted on an alkyl group having from 1 to 6 carbon atoms;the aryl group moiety may have one or more substituents selected fromthe group consisting of a halogen atom, a nitro group, an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms; and the alkyl group moiety may have one or moresubstituents selected from the group consisting of an alkyl group havingfrom 1 to 6 carbon atoms and an alkoxyl groups having from 1 to 6 carbonatoms), an acyl group (which may be either aliphatic or aromatic; in thecase of an aliphatic group, it has from 1 to 7 carbon atoms and may haveone or more substituents selected from the group consisting of an arylgroup, a halogen atom and an alkoxyl group having from 1 to 6 carbonatoms, wherein said aryl group may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and in the case of an aromatic group, thearomatic moiety is an aryl group, wherein said aryl group may have oneor more substituents selected from the group consisting of a halogenatom, a nitro group, an alkyl group having from 1 to 6 carbon atoms andan alkoxyl group having from 1 to 6 carbon atoms), an alkyloxycarbonylgroup having from 2 to 7 carbon atoms (the alkyl group moiety may haveone or more substituents selected from the group consisting of a halogenatom and an alkoxyl groups having from 1 to 6 carbon atoms), or anaralkyloxycarbonyl group (wherein the aralkyl group has a structure inwhich an aryl group is substituted on an alkyl group having from 1 to 6carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms); and R² represents a hydrogen atom, an alkyl group havingfrom 1 to 6 carbon atoms (which may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms), an aralkyl group (having astructure in which an aryl group is substituted on an alkyl group havingfrom 1 to 6 carbon atoms; the aryl group moiety may have one or moresubstituents selected from the group consisting of a halogen atom, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl groups having from 1 to 6 carbon atoms and analkoxyl groups having from 1 to 6 carbon atoms), an acyl group (whichmay be either aliphatic or aromatic; in the case of an aliphatic group,it has from 1 to 7 carbon atoms and may have one or more substituentsselected from the group consisting of an aryl group, a halogen atom andan alkoxyl group having from 1 to 6 carbon atoms; and in the cases of anaryl group as an aromatic group and an aryl group as a substituent onthe fatty chain in the case of an aliphatic group, it may have one ormore substituents selected from the group consisting of a halogen atom,a nitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms), an alkyloxycarbonylgroup having from 2 to 7 carbon atoms (the alkyl group moiety may haveone or more substituents selected from the group consisting of a halogenatom and an alkoxyl groups having from 1 to 6 carbon atoms), or anaralkyloxycarbonyl group (wherein the aralkyl group has a structure inwhich an aryl group is substituted on an alkyl group having from 1 to 6carbon atoms; the aryl group moiety may have one or more substituentsselected from the group consisting of a halogen atom, a nitro group, analkyl group having from 1 to 6 carbon atoms and an alkoxyl group havingfrom 1 to 6 carbon atoms; and the alkyl group moiety may have one ormore substituents selected from the group consisting of an alkyl grouphaving from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6carbon atoms), which comprises the following steps 1, 2 and 3, Step 1: astep in which an enantiomer mixture of a compound represented by aformula (I):

wherein R¹ and R² are as defined in the foregoing, and the substituentsR¹HN— and —CH₂HO on the pyrrolidine ring are in the cis configuration,is treated with a compound represented by formula (II):

wherein R³ and R⁴ each independently represents an alkyl group havingfrom 1 to 6 carbon atoms (which may have one or more substituentsselected from the group consisting of a halogen atom and an alkoxylgroup having from 1 to 6 carbon atoms), or an aralkyl group (having astructure in which an aryl group is substituted on an alkyl group havingfrom 1 to 6 carbon atoms; the aryl group moiety may have one or moresubstituents selected from the group consisting of a halogen atom, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms; and the alkyl groupmoiety may have one or more substituents selected from the groupconsisting of an alkyl group having from 1 to 6 carbon atoms and analkoxyl group having from 1 to 6 carbon atoms); or R³ and R⁴ maytogether form a cyclic structure of from five- to eight-membered ringcomprised of a polymethylene chain, in the presence of an acid as anoptically active compound, thereby obtaining a salt formed from acompound represented by a formula (IIIa):

and the optically active acid, Step 2: a step in which a free compoundis obtained by removing the acid from the salt formed from the compoundrepresented by formula (IIa) and the optically active acid, and Step 3:a step in which the compound represented by formula (Ia) is obtained byhydrolyzing free form of the compound represented by the formula (IIIa).14. The production method according to claim 13, wherein the acid as anoptically active compound is D-mandelic acid.
 15. The production methodaccording to any one of claims 11 to 14, wherein R³ and R⁴ are the samegroup.
 16. The production method according to any one of claims 11 to14, wherein R³ and R⁴ are a methyl group.
 17. The production methodaccording to any one of claims 11 to 14, wherein R¹ is a hydrogen atom.18. The production method according to any one of claims 11 to 14,wherein R² is selected from the group consisting of atert-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, abenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group, an acetyl group, a methoxyacetyl group,a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, aformyl group and a benzoyl group.
 19. The production method according toany one of claims 11 to 14, wherein R² is a benzyloxycarbonyl group.